Five-Year Follow-Up After Transcatheter Aortic Valve Implantation in Patients with Severe Aortic Stenosis and Concomitant Coronary Artery Disease: A Single-Center Experience

Introduction There is no consensus on the impact of coronary artery disease in patients undergoing transcatheter aortic valve implantation. Therefore, the objective of this study was, in a single-center setting, to evaluate the five-year outcome of transcatheter aortic valve implantation patients with or without coronary artery disease. Methods All transcatheter aortic valve implantation patients between 2009 and 2019 were included and grouped according to the presence or absence of coronary artery disease. The primary endpoint, five-year all-cause mortality, was evaluated using Cox regression adjusted for age, sex, procedure years, and comorbidities. Comorbidities interacting with coronary artery disease were evaluated with interaction tests. In-hospital complications was the secondary endpoint. Results In total, 176 patients had aortic stenosis and concomitant coronary artery disease, while 170 patients had aortic stenosis only. Mean follow-up was 2.2±1.6 years. There was no difference in the adjusted five-year all-cause mortality between transcatheter aortic valve implantation patients with and without coronary artery disease (hazard ratio 1.00, 95% confidence interval 0.59-1.70, P=0.99). In coronary artery disease patients, impaired renal function, peripheral arterial disease, or ejection fraction < 50% showed a significant interaction effect with higher five-year all-cause mortality. No significant differences in complications between the groups were found. Conclusion Five-year mortality did not differ between transcatheter aortic valve implantation patients with or without coronary artery disease. However, in patients with coronary artery disease and impaired renal function, peripheral arterial disease, or ejection fraction < 50%, we found significantly higher five-year all-cause mortality.


Abbreviations, Acronyms & Symbols
with CAD, leading to increased five-year all-cause mortality, was evaluated with interaction tests.The secondary endpoint was in-hospital complications.

Statistical Analysis
Differences in continuous baseline characteristics between the CAD and non-CAD groups were tested with unpaired t-test, and ordinal scale characteristics with Mann-Whitney U test.Non-ordered categorical baseline characteristics and number of complications were analysed with chi-square test or Fisher's exact test where appropriate.Unadjusted Kaplan-Meier and Cox regression analyses were used to visualize and evaluate time to mortality between the CAD and non-CAD groups.The patients were followed up until five years after the procedure, with no censored cases.Crude mortality rates per 1,000 person-years were presented, and adjusted Cox regression was performed in three models.

INTRODUCTION
Severe aortic stenosis (AS) is a common condition among the elderly, with a prevalence of 3.4% in patients > 75 years old [1] .With medical treatment only, the condition carries a poor prognosis, with a reported three-year all-cause mortality reported at 57% by one study [2] .Surgical aortic valve replacement (AVR) was the only available treatment in the past and has been shown to be superior to medical therapy even in asymptomatic patients [3] .Since it was first performed by Alain Cribier in humans in 2002, transcatheter aortic valve implantation (TAVI) has become an established treatment for severe AS [4][5][6][7] .
Coronary artery disease (CAD) and AS share similar associated clinical risk factors, such as older age, male sex, elevated lipoprotein levels, hypertension, and smoking [8,9] .The two conditions often concur, and CAD is prevalent in 30.8-78.2% of patients undergoing TAVI [10] .Patients with both severe AS and CAD undergoing surgical AVR have worse early and late survival compared with patients with severe AS alone [11] .The clinical impact of CAD in patients undergoing TAVI differs in previous reports.In a meta-analysis, Sankaramangalam et al. [10] (2017) found higher one-year mortality in patients with concomitant CAD, while data from the FRench Aortic National CoreValve and Edwards (FRANCE-2) registry showed similar death rates at a three-year follow-up [12] .Prior coronary artery bypass grafting (CABG) may unfavourably influence two-year outcome [13] , while prior percutaneous coronary intervention (PCI) does not [14] .The aim of this study was to evaluate five-year survival in TAVI patients with or without CAD in a single-center setting.

Study Design and Population
This retrospective observational study included all patients with severe AS undergoing TAVI between September 15, 2009, and November 29, 2019, at Örebro University Hospital (Örebro, Sweden).All included patients had intermediate to high surgical risk.Patients were divided into two groups according to the presence or absence of CAD.All patients underwent preoperative coronary angiography, except for a few cases where computed tomography angiography was performed.Patients with solitary stenosis or occlusion in a minor side branch were excluded from the study.Patients with spontaneous or iatrogenic coronary artery dissection were also excluded (Figure 1).The study was approved by the regional ethical review board (file number: 2019-06442).

Data Collection
Data were collected from patient files and the Swedish Transcatheter Cardiac Intervention Registry (SWENTRY), a sub-registry of the Swedish Web System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (or SWEDEHEART).In the SWENTRY, all consecutive patients, from all centers in Sweden, undergoing TAVI are registered.Total follow-up time was defined as the date of the procedure to December 1, 2019.Electronic health records with direct linkage to survival status were used to document survival and cause of death.The primary endpoint, five-year all-cause mortality, was assessed using Cox regression adjusted for age, sex, procedure years, and comorbidities.Presence of comorbidities interacting without prior coronary intervention.Baseline clinical characteristics are shown in Table 1.Significantly more patients in the CAD-AS group were males, and had PAD, a LVEF < 50%, hypertension, or a higher logistic EuroSCORE I.In the non-CAD group, more patients had CLD and elevated pulmonary artery pressure.

Five-Year All-Cause Mortality and Cause of Death
The mean total follow-up time was 2.2±1.6 years.Among patients with surgery before December  2) in all 346 patients.Cox regression revealed no differences in five-year all-cause mortality between patients with and patients without CAD in the three different adjustment models (Table 2).In the third adjusted model, HR was 1.00 (95% CI 0.59-1.70),but patients with eGFR < 50 ml/min/1.73m2 (HR 1.75 [95% CI 1.04-2.94])and CLD (HR 2.20 [95% CI 1.26-3.84])had a significantly increased mortality risk (Table 2).

Interaction Between Coronary Artery Disease and Comorbidities on Five-Year Mortality
Impaired renal function and presence of PAD showed a statistically significant interaction effect with CAD and mortality in all three adjusted models, with LVEF < 50% and age (≤ 79 vs. ≥ 80 years) Brazilian Journal of Cardiovascular Surgery  only in the second and third adjusted models and with CLD only in the first adjusted model (Table 3, Figures 3 to 5, and Supplementary Figures 1 and 2).Among patients with impaired renal function, the HR was 2.90 (95% CI 1.09-7.77)when comparing the CAD and non-CAD group in the third adjusted model.Among patients with PAD, the HR was 5.97 (95% CI 1.41-25.2);however, the hazard was non-proportional and because of few mortality cases it was not possible to evaluate only the first year of follow-up.Among patients with LVEF < 50%, the HR was 2.24 (95% CI 0.86-5.85)when comparing the CAD and non-CAD group.Among patients aged < 80 years, the HR was 1.78 (95% CI 0.81-3.90)but the hazard was non-proportional, and for the first year of follow-up, the HR was 6.19 (95% CI 1.30-29.5).Among patients with CLD, the HR was 1.95 (95% CI 0.80-4.78)(Table 3).

DISCUSSION
In this single-center observational study, we did not find differences in five-year mortality between patients with AS and CAD, and patients with AS alone undergoing TAVI.However, renal impairment, PAD, LVEF < 50%, and age ≥ 80 years in addition to CAD were associated with significantly higher five-year mortality.
The five-year all-cause mortality of 52.5% in our study is in line with previous studies reporting a mortality rate between 41.0% and 67.8% [4,15] .The proportion of CAD patients, 50.9%, is also consistent with a previously conducted meta-analysis [10] .At baseline, patients with CAD had a significantly higher logistic EuroSCORE I and more cardiovascular risk factors.Despite this, the CAD group had a similar five-year all-cause mortality.Most previous studies investigating the impact of CAD on TAVI outcomes report follow-up times of no longer than three years.The populations and definitions of CAD in these studies have differed.Kawashima et al. [13] found that TAVI patients with previous CABG had a higher rate of two-year all-cause mortality and cardiovascular death.However, in their study, CAD was also present in the group without prior CABG.Results from the FRANCE-2 registry showed that CAD was not associated with increased mortality at 30 days or three years but the authors found that stenosis of the left anterior descending coronary artery was associated with higher three-year mortality [12] .One important factor to note is that patients with prior CABG were excluded from their study, which may explain why the prevalence of CAD was lower, at 36%.Two meta-analyses on the subject reached different conclusions: Sankaramangalam et al. [10] in 2017 studied the impact of CAD (n=3,899) in patients (n=8,013) undergoing a TAVI procedure and showed that the CAD group had a significantly lower survival at one year.In the same year, Kotronias et al. [14] investigated the effect of previous PCI (n=983) vs. no previous PCI in TAVI patients (n=3,858) on one-year all-cause mortality.They found no differences between groups.
In another report, impaired renal function with eGFR < 60 ml/ min/1.73m 2 was not associated with increased death rates at one year after TAVI [17] .Impaired renal function in our study (eGFR ) was not associated with increased five-year mortality but the interaction between CAD and impaired renal failure was significant and associated with higher five-year mortality.The total prevalence of PAD was 22.1% and 10.0% in the CAD and non-CAD groups, respectively.This is in line with previous studies reporting a prevalence of 19.2-25.1% [18,19] .PAD has been associated with increased early (< 30 days) and late (> 12 months) mortality after TAVI [18,20] .Such association was only seen when the interaction between PAD and CAD was analysed in our study.There were more patients with PAD in the CAD than in the non-CAD group, which was unsurprising given the overlap of risk factors.
Pulmonary hypertension and impaired LVEF in patients with AS are common indicators of advanced disease usually resulting in poor prognosis [21,22] .Contradicting other reports [21,23] , in our study neither of these comorbidities alone had an impact on five-year mortality.CLD was the only isolated comorbidity associated with higher five-year mortality after TAVI.This finding is supported by previous studies [24] and may prove helpful in future patient selection.
Until recently, and before the publication of the low-risk TAVI trials [6,7] , TAVI was mainly reserved for elderly patients with intermediate or high operative risk.With this in mind, we studied the interaction between CAD and age ≥ 80 years and found higher five-year Our study is a small contribution to the current evidence gap of TAVI patients with CAD and is in line with an ongoing trialthe COMPLETE TAVR (ClinicalTrials.gov:NCT04634240).Additionally, our data shows similar results as the newly published study from the percutAneous Coronary inTervention prIor to transcatheter aortic VAlve implantation (or ACTIVATION) trial; similar observed rates of death and rehospitalizations at 1 year between PCI and no PCI prior to TAVI [25] , albeit their time frame of one year differs from our five years.

Limitations
There is a risk for bias in this observational study, mainly due to the selection and classification of patients, potential confounding factors not accounted for in our analysis in addition to bias for missing data.Missing data in the registry were addressed through reviewing and adding data from the individual patient's electronic health records.However, not all missing data were accounted for using this method.As this was a single-center study, the number

Fig. 2 -
Fig. 2 -Unadjusted Kaplan-Meier curve showing the five-year survival for transcatheter aortic valve implantation patients with or without coronary artery disease (CAD).CI=confidence interval; HR=hazard ratio.

Table 1 .
Patients' characteristics and comorbidities of the coronary artery disease (CAD) and non-CAD groups at baseline.

Table 2 .
Cox regression analysis of mortality and comorbidities in the coronary artery disease (CAD) group and the non-CAD group.

Table 3 .
Cox regression analysis of mortality stratified to different comorbidities and age in the coronary artery disease (CAD) group vs. the non-CAD group.